This program project is designed to mount a multidisciplinary study of the interplay among cholinergic, dopaminergic and other neurotransmitter systems in basal ganglia and the effects that alterations in these systems have on extrapyramidal motor function and behavior. In particular, the mechanisms will be investigated by which adverse reactions develop; such as, dyskinesias and "on-off" phenomenon with chronic L-dopa therapy, and the tardive dyskinesias associated with chronic neuroleptic treatment. The effects of L-dopa, dopaminergic agonists, dopamine receptor blocking agents, cholinergic agonists and cholinergic blocking agents on motor function and various psychological parameters will be determined in normal human subjects, patients with extrapyramidal disorders and schizophrenic patients. Attempts will be made to determine whether levels of CSF or urinary dopamine or metabolites may be reliable predictors of adverse reactions to neuroleptics. Employing rats and rats subjected to nigral lesions, studies will be performed on the effects on neostriatal function of chronic administration of L-dopa, dopamine agonists, dopamine receptor blocking agents and cholinergic agonists and antagonists, with regard to possible alterations in: the electrophysiological response of caudate neurons; the number or sensitivities of postsynaptic receptors; responses to neurotransmitters of caudate adenylate and guanylate cyclases; and levels, activity and subcellular distribution of tyrosine hydroxylase and other neurotransmitter biosynthetic enzymes of the neostriatum. Parallel studies of the effects of these various pharmacological agents on the electrophysiology and biochemistry of substantia nigra, caudate and combined nigral and striatal tissues transplanted from fetal brains into the anterior chamber of the eye will be conducted.